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Dynamic Enolate Recognition in Aqueous Solution by Zinc(II) in a Phenacyl-Pendant Cyclen Complex:  Implications for the Role of Zinc(II) in Class II Aldolases

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posted on 02.02.1999, 00:00 by Eiichi Kimura, Teruhiro Gotoh, Tohru Koike, Motoo Shiro
A zinc(II) complex of 1-(4-bromophenacyl)-1,4,7,10-tetraazacyclododecane, ZnL, has been synthesized to mimic the active center of class II aldolases. Its X-ray crystal structure showed that zinc(II) remains atop the four nitrogen atoms of cyclen (average Zn−N distance 2.170 Å) to bind with the carbonyl oxygen (Zn−O distance of 2.159(3) Å) and one H2O (Zn−O distance of 2.130(3) Å). Crystal data:  monoclinic, space group P21/n (No. 14), with a = 12.221(8) Å, b = 11.052(7) Å, c = 18.194(9) Å, β = 97.12(3)°, V = 2438(5) Å3, Z = 4, R = 0.041, and Rw = 0.046. The potentiometric pH titration of ZnL in aqueous solution disclosed dissociation of one proton with pKa = 8.41 at 25 °C and I = 0.1 (NaClO4), which yields a mixture of a hydroxide-bound complex (ZnL−OH-) and an enolate-bound complex (ZnH-1L) in a 3:1 ratio, as determined by UV spectrophotometric and 13C and 1H NMR titrations. This is the first quantitative assessment of enolate formation promoted by a proximate zinc(II) ion near neutral pH in aqueous solution. The enolate-bound complex ZnH-1L independently isolated by treatment of ZnL with an equivalent amount NaOMe in acetonitrile was fully characterized to compare with ZnL. The equilibrium between the ZnL−OH- and ZnH-1L varied with temperature (15, 25, and 35 °C), from which thermodynamic parameters of ΔG = 3.0 kJ mol-1, ΔH = 8.7 kJ mol-1, and ΔS = 19 J mol-1 K-1 at 25 °C were determined. Because of the facile enolization by zinc(II), the methylene hydrogen atoms (adjacent to the carbonyl) of ZnL were readily exchanged by deuterium under physiological conditions. The half-life at 25 °C for this H−D exchange at pD 7 (20 mM MOPS buffer) was determined to be 25 min by 1H NMR measurements. Implications of the present results for the role of zinc(II) in the active center of class II aldolases are discussed.